Choline Derivate-Modified Doxorubicin Loaded Micelle for Glioma Therapy

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• 作者：Jianfeng Li ; Huiying Yang ; Yujie Zhang ; Xutao Jiang ; Yubo Guo ; Sai An ; Haojun Ma ; Xi He ; Chen Jiang
• 刊名：ACS Applied Materials & Interfaces
• 出版年：2015
• 出版时间：September 30, 2015
• 年：2015
• 卷：7
• 期：38
• 页码：21589-21601
• 全文大小：969K
• ISSN：1944-8252

文摘

Ligand-mediated polymeric micelles have enormous potential for improving the efficacy of glioma therapy. Linear鈥揹endritic drug鈥損olymer conjugates composed of doxorubicin (DOX) and polyethylene glycol (PEG) were synthesized with or without modification of choline derivate (CD). The resulting MeO鈥揚EG鈥揇OX₈ and CD鈥揚EG鈥揇OX₈ could self-assemble into polymeric micelles with a nanosized diameter around 30 nm and a high drug loading content up to 40.6 and 32.3%, respectively. The optimized formulation 20% CD鈥揚EG鈥揇OX₈ micelles had superior cellular uptake and antitumor activity against MeO鈥揚EG鈥揇OX₈ micelles. The subcellular distribution using confocal study revealed that 20% CD鈥揚EG鈥揇OX₈ micelles preferentially accumulated in the mitochondria. Pharmacokinetic study showed area under the plasma concentration鈥搕ime curve (AUC_0鈥?i>t) and C_max for 20% CD鈥揚EG鈥揇OX₈ micelles and DOX solution were 1336.58 卤 179.43 mg/L路h, 96.35 卤 3.32 mg/L and 1.40 卤 0.19 mg/L路h, 1.15 卤 0.25 mg/L, respectively. Biodistribution study showed the DOX concentration of 20% CD鈥揚EG鈥揇OX₈ micelles treated group at 48 h was 2.37-fold higher than that of MeO鈥揚EG鈥揇OX₈ micelles treated group at 48 h and was 24 fold-higher than that of DOX solution treated group at 24 h. CD鈥揚EG鈥揇OX₈ micelles (20%) were well tolerated with reduced cardiotoxicity, as evaluated in the body weight change and HE staining studies, while they induced most significant antitumor activity with longest media survival time in an orthotopic mouse model of U87-luci glioblastoma model as displayed in the bioluminescence imaging and survival curve studies. Our findings consequently indicated that 20% CD鈥揚EG鈥揇OX₈ micelles are promising drug delivery system for glioma chemotherapy.